HALAVEN
®
(eribulinmesylate) InjectionBRIEFSUMMARY–Seepackage insert for fullprescribing information.
2.2
Dose Modification
Assess forperipheralneuropathyandobtaincompletebloodcellcountsprior toeachdose.
Recommendeddosedelays
• Do not administer HALAVEN on Day 1 or Day 8 for any of the following:
– ANC <1,000/mm
3
– Platelets <75,000/mm
3
– Grade 3 or 4 non-hematological toxicities.
• TheDay8dosemaybedelayed foramaximumof1week.
– If toxicitiesdonot resolveor improve to≤Grade2severitybyDay15,omit thedose.
– If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate
thenextcyclenosooner than2weeks later.
Recommendeddose reductions
• Ifadosehasbeendelayed for toxicityand toxicitieshave recovered toGrade2severityor less, resumeHALAVENata reduced
doseassetout inTable1.
• Donot re-escalateHALAVENdoseafter ithasbeen reduced.
Table 1 Recommended Dose Reductions
Event Description
Recommended
HALAVEN Dose
Permanently reduce the 1.4 mg/m
2
HALAVEN dose for any of the following:
1.1 mg/m
2
ANC <500/mm
3
for >7 days
ANC <1,000 /mm
3
with fever or infection
Platelets <25,000/mm
3
Platelets <50,000/mm
3
requiring transfusion
Non-hematologic Grade 3 or 4 toxicities
Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity
Occurrence
of any event requiring permanent dose reductionwhile receiving 1.1 mg/m
2
0.7 mg/m
2
Occurrence
of any event requiring permanent dose reductionwhile receiving0.7mg/m
2
Discontinue HALAVEN
ANC=absoluteneutrophilcount.
Toxicitiesgraded inaccordancewithNationalCancer Institute (NCI)CommonTerminologyCriteriaforAdverseEvents (CTCAE)version3.0.
5
WARNINGS AND PRECAUTIONS
5.1
Neutropenia
Severe neutropenia (ANC <500/mm
3
) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to
discontinuation in<1%ofpatients.Patientswithalanineaminotransferaseoraspartateaminotransferase>3
×
ULN (upper limit
ofnormal)experiencedahigherincidenceofGrade4neutropeniaandfebrileneutropeniathanpatientswithnormalaminotransferase
levels.Patientswithbilirubin>1.5
×
ULNalsohadahigher incidenceofGrade4neutropeniaand febrileneutropenia.
Monitorcompletebloodcountspriortoeachdose;increasethefrequencyofmonitoringinpatientswhodevelopGrade3or4cytopenias.
DelayadministrationofHALAVENandreducesubsequentdosesinpatientswhoexperiencefebrileneutropeniaorGrade4neutropenia
lasting longerthan7days.ClinicalstudiesofHALAVENdidnot includepatientswithbaselineneutrophilcountsbelow1,500/mm
3
.
5.2
Peripheral Neuropathy
Grade3peripheralneuropathyoccurred in8% (40/503)ofpatients,andGrade4 in0.4% (2/503)ofpatients inStudy1.Peripheral
neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy
lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new
or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor
patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3
or4peripheralneuropathyuntil resolution toGrade2or less.
5.3
Embryo-Fetal Toxicity
There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor;
therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity
occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface
area. If thisdrug isusedduringpregnancy,or ifapatientbecomespregnantwhile taking thisdrug,sheshouldbeapprisedof the
potentialhazard to the fetus.
5.4
QT Prolongation
In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin
concentration,withnoQTprolongationobservedonDay1.ECGmonitoring isrecommended iftherapy is initiated inpatientswith
congestiveheartfailure,bradyarrhythmias,drugsknowntoprolongtheQT interval, includingClass Iaand IIIantiarrhythmics,and
electrolyteabnormalities.Correcthypokalemiaorhypomagnesemiaprior to initiatingHALAVENandmonitor theseelectrolytes
periodicallyduring therapy.AvoidHALAVEN inpatientswithcongenital longQTsyndrome.
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
The following adverse reactions are discussed in detail in other sections of the labeling:
• Neutropenia • Peripheral neuropathy • QT interval prolongation
The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/
fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in
patients receivingHALAVENwere febrileneutropenia (4%)andneutropenia (2%).Themostcommonadverse reaction resulting
indiscontinuationofHALAVENwasperipheralneuropathy (5%).
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials
ofadrugcannotbedirectlycompared to rates inotherclinical trialsandmaynot reflect the ratesobserved inclinicalpractice.
Inclinical trials,HALAVENhasbeenadministered to1,222patientswithmultiple tumor types, including240patientsexposed to
HALAVEN for6monthsor longer.Themajorityof the1,222patientswerewomen (82%)withamedianageof58years (range:26
to91years).The racialandethnicdistributionwasCaucasian (83%),Black (5%),Asian (2%),andother (5%).
Theadversereactionsdescribed inTable2were identified in750patientstreated inStudy1. InStudy1,patientswererandomized
(2:1) to receiveeitherHALAVEN (1.4mg/m
2
onDays1and8ofa21-daycycle)orsingleagent treatmentchosenby theirphysician
(control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting
of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other
chemotherapies10%)]orhormonaltherapy (3%).Themediandurationofexposurewas118daysforpatientsreceivingHALAVEN
and63days forpatients receivingcontrol therapy.Table2 reports themostcommonadverse reactionsoccurring inat least10%
ofpatients ineithergroup.
Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1
MedDRAver10.0
HALAVEN (n=503)
ControlGroup (n=247)
AllGrades ≥Grade3 AllGrades ≥Grade3
BloodandLymphaticSystemDisorders
a
Neutropenia
82%
57% 53%
23%
Anemia
58%
2% 55%
4%
Nervoussystemdisorders
Peripheralneuropathy
b
35%
8% 16%
2%
Headache
19%
<1% 12%
<1%
Generaldisordersandadministrativesiteconditions
Asthenia/Fatigue
54%
10% 40%
11%
Mucosal inflammation
9%
1% 10%
2%
Pyrexia
21%
<1% 13%
<1%
Gastrointestinaldisorders
Constipation
25%
1% 21%
1%
Diarrhea
18%
0
18%
0
Nausea
35%
1% 28%
3%
Vomiting
18%
1% 18%
1%
Musculoskeletalandconnective tissuedisorders
Arthralgia/Myalgia
22%
<1% 12%
1%
Backpain
16%
1% 7%
2%
Bonepain
12%
2% 9%
2%
Pain inextremity
11%
1% 10%
1%
Investigations
Weightdecreased
21%
1% 14%
<1%
Metabolismandnutritiondisorders
Anorexia
20%
1% 13%
1%
Respiratory, thoracic,andmediastinaldisorders
Cough
14%
0
9%
0
Dyspnea
16%
4% 13%
4%
Skinandsubcutaneous tissuedisorders
Alopecia
45%
NA
c
10%
NA
c
Table 2 (cont'd)
MedDRA ver 10.0
HALAVEN (n=503)
Control Group (n=247)
All Grades ≥ Grade 3 All Grades ≥ Grade 3
Infections and Infestations
Urinary Tract Infection
10%
1%
5%
0
a
basedupon laboratorydata.
b
includesneuropathyperipheral,neuropathy,peripheralmotorneuropathy,polyneuropathy,peripheralsensoryneuropathy,andparaesthesia.
c
notapplicable; (gradingsystemdoesnotspecify>Grade2 foralopecia).
Cytopenias:Grade3neutropeniaoccurred in28% (143/503)ofpatientswho receivedHALAVEN inStudy1,and29% (144/503)
ofpatientsexperiencedGrade4neutropenia.Febrileneutropeniaoccurred in5% (23/503)ofpatients; twopatients (0.4%)died
from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and
discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from
severe neutropenia (<500/mm
3
) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF
(granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of
patientswho receivedHALAVEN.
PeripheralNeuropathy: InStudy1,17%ofenrolledpatientshadGrade1peripheralneuropathyand3%ofpatientshadGrade2
peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who
receivedHALAVEN.Fourpercent (20/503)ofpatientsexperiencedperipheralmotorneuropathyofanygradeand2% (8/503)of
patientsdevelopedGrade3peripheralmotorneuropathy.
Liver Function Test Abnormalities:Among patients with Grade 0 or1 ALT levels at baseline,18% of HALAVEN-treated patients
experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had
concomitantGrade2elevations inbilirubinandALT;theseabnormalities resolvedanddidnot recurwithre-exposuretoHALAVEN.
Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the
HALAVEN-treatedgroup:
EyeDisorders:
increased lacrimation;
GastrointestinalDisorders:
dyspepsia,abdominalpain,
stomatitis, dry mouth;
General Disorders and Administration Site Conditions:
peripheral edema;
Infections and
Infestations:
upper respiratory tract infection;
MetabolismandNutritionDisorders:
hypokalemia;
Musculoskeletal
and Connective Tissue Disorders:
muscle spasms, muscular weakness;
Nervous System Disorders:
dysgeusia,
dizziness;
PsychiatricDisorders:
insomnia,depression;
SkinandSubcutaneousTissueDisorders:
rash.
6.2
Postmarketing Experience
The following adverse drug reactions have been identified during post-approval of HALAVEN. Because these reactions are
reportedvoluntarily fromapopulationofuncertainsize, it isnotalwayspossible to reliablyestimate their frequencyorestablish
a causal relationship to drug exposure.
Blood and Lymphatic System Disorders:
lymphopenia;
Gastrointestinal
Disorders:
pancreatitis;
Hepatobiliary Disorders:
hepatotoxicity;
Immune System Disorders:
drug hypersensitivity;
Infections and Infestations:
pneumonia, sepsis/neutropenic sepsis;
Metabolism and Nutrition Disorders:
hypomagnesemia, dehydration;
Respiratory, thoracic, and mediastinal disorders:
interstitial lung disease;
Skin and
Subcutaneous Tissue Disorders:
pruritus.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy Category D
There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor;
therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity
occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface
area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
apprisedof thepotentialhazard to the fetus.
Inadevelopmental toxicitystudy,pregnant rats received intravenous infusionoferibulinmesylateduringorganogenesis (Gestation
Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface
area(mg/m
2
).Increasedabortionandsevereexternalorsofttissuemalformationswereobservedinoffspringatdoses0.64timesthe
recommendedhumandosebasedonbodysurfacearea (mg/m
2
), includingtheabsenceofa lower jaw,tongue,stomachandspleen.
Increasedembryo-fetaldeath/resorption,reducedfetalweights,andminorskeletalanomaliesconsistentwithdevelopmentaldelay
werealso reportedatorabovedosesof0.43 times the recommendedhumandose.
Maternal toxicityoferibulinmesylatewas reported in ratsatorabovedosesof0.43 times the recommendedhumandose (mg/m²),
and includedenlargedspleen, reducedmaternalweightgainanddecreased foodconsumption.
8.3
Nursing Mothers
It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine
if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious
adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to
discontinueHALAVEN taking intoaccount the importanceof thedrug to themother.
8.4
Pediatric Use
ThesafetyandeffectivenessofHALAVEN inpediatricpatientsbelow theageof18yearshavenotbeenestablished.
8.6
Hepatic Impairment
Administration of HALAVEN at a dose of 1.1 mg/m
2
to patients with mild hepatic impairment and 0.7 mg/m
2
to patients with
moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m
2
to patients with normal hepatic
function.Therefore,a lowerstartingdoseof1.1mg/m
2
is recommended forpatientswithmildhepatic impairment (Child-PughA)
and of 0.7 mg/m
2
is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in
patientswithseverehepatic impairment (Child-PughC).
8.7
Renal Impairment
For patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure
increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m
2
is recommended for
patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment
(CrCl<30mL/min).
10
OVERDOSAGE
Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3
neutropenia lastingsevendaysandaGrade3hypersensitivity reaction lastingoneday.
There isnoknownantidote forHALAVENoverdose.
12
CLINICAL PHARMACOLOGY
12.3
Pharmacokinetics
Specific Populations
Hepatic Impairment
Astudyevaluated thePKoferibulin inpatientswithmild (Child-PughA;n=7)andmoderate (Child-PughB;n=5)hepatic impairment.
Compared topatientswithnormalhepatic function (n=6),eribulinexposure increased1.8-foldand2.5-fold inpatientswithmildand
moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m
2
to patients with mild hepatic
impairment and 0.7 mg/m
2
to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of
1.4mg/m
2
topatientswithnormalhepatic function.
Renal Impairment
No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that geometric
mean dose-normalized systemic exposure is similar for patients with mild renal impairment (CrCl 50-80 mL/min) relative to
patientswithnormal renal function.However, forpatientswithmoderate renal impairment (CrCl30-50mL/min), thegeometric
meandose-normalizedsystemicexposure increased2-foldcompared topatientswithnormal renal function.
12.6
Cardiac Electrophysiology
The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated
QT trial.A totalof26patientswithsolid tumors received1.4mg/m
2
ofHALAVENonDays1and8ofa21-daycycle.Adelayed
QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from
baseline (95% upper confidence interval) was 11.4 (19.5) ms.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, mutagenesis, impairment of fertility
Carcinogenicitystudieshavenotbeenconductedwitheribulinmesylate.
Eribulinmesylatewasnotmutagenic in
invitro
bacterial reversemutationassays (Ames test).Eribulinmesylatewaspositive in
mouse lymphomamutagenesisassays,andwasclastogenic inan
invivo
ratbonemarrowmicronucleusassay.
The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in
humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility
may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous
epitheliumwithhypospermia/aspermia)followingdosingwitheribulinmesylateatorabove0.43timestherecommendedhuman
dose (mg/m
2
)givenonceweeklyfor3weeks,oratorabove0.21timestherecommendedhumandose (mg/m
2
)givenonceweekly
for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended
humandose (mg/m
2
)weekly for3outof5weeks, repeated for6cycles.
17
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling
• Advisepatients tocontact theirhealthcareprovider fora feverof100.5°Forgreaterorothersignsorsymptomsof infectionsuch
aschills,cough,orburningorpainonurination.
• AdvisewomenofchildbearingpotentialtoavoidpregnancyandtouseeffectivecontraceptionduringtreatmentwithHALAVEN.
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
HALAVEN
®
isa registered trademarkusedbyEisai Inc.under license from EisaiR&DManagementCo.,Ltd.
©2014Eisai Inc.All rights reserved.Printed inUSA/August2014 HALA0671
